Transdermal estrogen/progestin dosage unit, system and process

ABSTRACT

Transdermal estrogen/progestin absorption dosage unit have been developed which comprise a backing layer, an adjoining polymer layer is an adhesive layer in which at least minimum effective dose of an estrogen is dissolved or microdispersed. Adhered to the polymer layer in an adhesive layer in which is dissolved and/or microdispersed at least minimum doses of progestin. Presently preferred is use of the natural estrogen, 17-beta-estradiol, or ethinyl estradiol or combinations thereof and of the progestin, norethindrone or norgestimate or combinations thereof. The units have biologically acceptable adhesive and polymer layers. The adhesive layer can have dispersed one or more skin permeation enhancing agents. A separating layer can optionally be used in making the dosage units, which separate space the adhesive and polymer layers, which permits estrogen tansmission from the polymer layer during treatment. Dosage units are provided which transdermally deliver at least minimum daily doses of the estrogen and progestin for multiple days, such as for one week. The invention also provides a process of fertility control and estrogen replacement therapy using the novel dosage units. Also, the invention provides a fertility control system for fertility control using the novel dosage units.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of U.S. application Ser. No.947,130, filed December 29, 1986, now abandoned.

TECHNICAL FIELD

This invention relates to a novel transdermal fertility control systemand a process for controlling fertility. The system involves transdermalestrogen/progestin absorption dosage units adapted for adhesion to thefemale subject desiring fertility control or prevention of an unwantedpregnancy. Additionally, the invention relates to a method ofcontrolling fertility by utilizing a transdermal system of applying aseries of transdermal estrogen/progestin dosage units having a polymerlayer adhered to a backing layer and an adhesive layer adhered to thepolymer layer, said polymer and adhesive layer having dissolved and/ormicrodispersed therein estrogen and progestin, respectively, ineffective dosage amounts. Preferably, the estrogen used isbeta-estradiol or ethinyl estradiol and the progestin used isnorethindrone or norgestimate. The dosage units can also be used inestrogenic replacement therapy.

BACKGROUND ART

Estrogenic therapies include two main areas, fertility control andestrogenic replacement.

Fertility has been controlled by use of a number of orally administeredhormone products. The products are ordinarily a combination of anestrogen and a progestin. A synthetic estrogen is ordinarily used as theestrogen component since the natural estrogen, 17-beta-estradiol, isalmost completely destroyed, usually by over 90 percent, when takenorally. It is destroyed to a degree in the digestive tract before it isabsorbed but primarily the destructive metabolism of 17-beta-estradioloccurs during the first pass hepatic metabolism. Since such a largeamount is destroyed, in order to provide an effective dosage orally, alarge excess must be administered with uncertain effectiveness and alarge amount of unwanted metabolic products. Therefore, a syntheticestrogen such as ethinyl estradiol normally is orally administered withless than desired results.

The progestin component generally inhibits, as intended, ovulation.Also, in the case of administered progestin, a substantial amount ofmetabolic breakdown occurs causing undesired metabolic products withundesired effects.

Therefore, in the oral administration of what is commonly referred to as"the pill" or other orally administered products, considerablyoverdosing is necessary to obtain a high degree of assurance that thedesired fertility control will be obtained.

A number of major side effects have reportedly been associated with theadministration of oral fertility control preparations, such asthrombophlebitis and thrombosis, pulmonary embolism, coronarythrombosis, myocardial infarction, cerebral thrombosis, cerebralhemorrhage and hypertension. These side effects have been attributed tothe estrogen component in the oral preparations. Use of theprogestin-only preparations (mini-pill) has been found to eliminate theside effects of estrogen. However, the fertility control is less thanthat of the combined preparations and the menstrual cycle also becomesmore irregular. It has been reported that less incidence of irregularbleeding is observed if the progestin is administered at a more constantrate of delivery. Besides the side effects, the oral fertility controlpreparations also have the disadvantage of fertility control efficacydepending highly on the degree of patient compliance. The risk ofpregnancy is known to increase with each pill missed.

An ideal and patient-acceptable fertility control system should providethe following advantages: minimized side effect, increased ease ofadministration, rapid termination of treatment, if needed, and improvedpatient compliance. In recent years, considerable attention has alreadybeen directed to the development of implantable, intrauterine,intracervical or intravaginal fertility control delivery systems toprovide a prolonged and controlled administration of steroidal hormonesto the body for achieving fertility control; however, none of thedelivery systems developed so far can be considered as ideal and sideeffect-free.

Other fertility control means have been used, such as topical creams andintravaginal devices, which deliver combinations of one or moreprogestins and one or more estrogens, including the naturally-occurringestrogen, 17-beta-estradiol. However, the undersirable aspects of suchfertility control systems are evident.

It is, therefore, highly desired that transdermal systems be providedwhich permit (1) use of the natural estrogen, 17-beta-estradiol, ifdesired, (2) use of a minimum number of dosage units for each menstrualcycle, such as use of three successive weekly dosage units, and (3)adherence to the skin of the subject which would administer sufficientlyhigh levels of estrogen and progestin hormones to provide high assuranceof fertility control without a high amount of undesired metabolic orchemical degradative products. Development of a rate-control transdermaldrug delivery system, which is capable of minimizing any individualvariability and regional differences in skin permeability, is anecessity to attain a predictable blood level of a drug. The transdermalrate-control drug administration is known to offer several potentialadvantages for systemic medication: (i) avoidance of the risk andinconvenience of intravenous therapy and of the variability inabsorption and metabolism associated with oral therapy; (ii) continuityof drug administration, permitting the use of a pharmacologically-activeagent with short biological half-life; (iii) efficacy can be achievedwith lower total daily dosage of drug, because of reduced hepaticfirst-pass metabolism and continuous drug input; (iv) less chance ofover- or under-dosing, as a result of prolonged, programmed delivery ofdrug at required therapeutic rate; (v) provision of a simplifiedmedication regimen; and (vi) ability to rapidly terminate the druginfusion, if needed, by removal of the drug delivery system from skinsurface. Therefore, a transdermal contraceptive delivery system, whichis capable of providing on a fast effective basis dual-delivery of anestrogen and a progestin at controlled rates for a specific durationwould be an ideal system for achieving fertility regulation in women.

The second main area of estrogenic therapy concerns the need forestradiol replacement therapy. It is caused by menopause (the cessationof ovarian function), oophorectomy (loss of one or both ovaries bysurgery) or by pituitary failure. Replacement estrogenic therapy is animportant need. Besides the need to alleviate the menopausal symptomscaused by estrogenic steroid deficiency, there are additionalcontributions of such replacement estrogenic therapy associated withosteoporosis (loss of bone mass) and atherosclerosis. It has been foundadvantageous to administer also an amount of progestin as a part of suchestrogenic replacement therapy. There is clearly a need for improvementsin means and methods for estrogenic steroid therapy. Even though it hasbeen found that estradiol itself or estradiol in the form of certainderivatives such as nonoor diesters (e.g., acetate esters) can beabsorbed transdermally, it is desired that improved transdermalestradiol and other estrogenic steroid absorption dosage unit forms andprocesses of transdermal administration be developed.

SUMMARY OF INVENTION

Provided by this invention is a transdermal fertility control absorptionsystem which permits fertility control by using sequentially threetransdermal adhesive dosage units which can easily be applied to aselected skin area.

The first patch ordinarily is applied on the fifth day of a menstrualcycle. The dosage unit is replaced by the second unit after 7 days andthe second is replaced by a third at the end of another 7 days. Then, atthe beginning of the next menstrual cycle, another sequential course of3 fertility control patches is again used, which course is repeatedagain and again as long as desired.

The transdermal estrogen/progestin dosage units of this inventioncomprise:

(a) a backing layer which is substantially impervious to the estrogenand progestin hormones to be delivered transdermally and whichoptionally is breathable, especially if the dosage unit is used on along-term basis, such as for several days;

(b) a polymer layer which is in contact with said backing layer andwhich has dissolved and/or microdispersed therein an effective amount ofan estrogen, preferably 17-beta-estradiol, ethynyl estradiol, orcombinations thereof, said polymer layer providing a dosage amount ofthe estrogen to be delivered transdermally; and

(c) an adhesive layer which can adhere the dosage unit in intimatecontact with the skin of the subject being treated to permit thehormones to be absorbed transdermally, said adhesive layer being adheredto the polymer layer and having dissolved and/or microdispersed thereinan effective dosage amount of a progestin, preferably norethindrone,norgestimate or combinations thereof, said adhesive layer beingbioacceptable and permitting said progestin and said estrogen to betransmitted for transdermal absorption, said adhesive layer having aneffective amount of a skin absorption enhancing agent.

Optionally, another layer can be included in the dosage units betweenthe polymer layer (b) which has present an estrogen and the adhesivelayer (c) which has present a progestin. In this separating layer, it ispreferable to have present little or no estrogen or progestin. Theseparating layer can be made of adhesive polymers such as used in makingadhesive layer (c), with a bioacceptable polyisobutylene which permitsthe estrogen in layer (b) to be transmitted for transdermal absorptionbeing presently preferred. Additionally, it is presently preferred thatthe separating layer be free of any substantial amount of skinabsorption enhancing agent.

The estrogen dissolved or microdispersed in the polymer layer comprisesan amount of 17-beta-estradiol or ethinyl estradiol effective inproviding the role of estrogen in fertility control or in estrogenreplacement and norethin-drone or norgestimate dissolved ormicrodispersed in the adhesive layer comprises an amount which willprovide the role of progestin in the desired fertility control system orin estrogen replacement. Desirably, the dosage units will provide thedesired rate of transdermal absorption of the estrogen and progestincomponents for a period of several days, preferably for one week. Use ofweek-long transdermal dosage units minimize the possibility of missedadministration of a dosage in fertility control.

The backing layer is made from materials that are substantiallyimpermeable with regard to the hormones of the transdermal dosage unit.It can be made of polymers such as polyethylene, polypropylene,polyurethane, polyvinyl-chloride, polyesters such as poly(ethylenephthalate), and foils such as laminates of polymer films with metallicfoils such as aluminum foil. If the dosage units are used on a long termbasis, such as for a multiple of days, the backing preferably has amicroporosity to permit passage of sweat and air to minimize any skinhydration.

The polymer disc layer is suitably fabricated from biologicallyacceptable lipophilic or hydrophilic polymers, which will permit theestrogen to be transmitted for transdermal absorption and which providecompatibility and stability for the estrogen. The polymer layer whichhas the estrogen distributed therein can preferably be made of asuitable polymeric adhesive, such as a suitable polyacrylic or asilicone adhesive in which the estrogen is stable and microdispersibleor soluble. The polymer layer can also be made using a polymer tofabricate a disc in which the estrogen is microdispersed. Thepolymer-estrogen mixture is then formed into a layer of an appropriatethickness and suitable surface area and is cured, if desired. Thepolymer disc layer is then adhered to the backing layer. Care must betaken that the polymer selected is compatible with the pharmaceutical,permits its release for transdermal absorption and is free orsufficiently free from any biologically unacceptable components.

Other estrogenic steroid hormones can be used in partial or completereplacement of 17-beta-estradiol, for example, an ester of 17-betaestradiol which is biologically compatible and can be effectivelyabsorbed transdermally and at a rate compatible with the rate ofabsorption of progestin. Also, it is ordinarily desired that such estersare bioconvertible by components of the skin or other portions of thebody, such as hydrolytical enzymes (e.g., esterase), to17-beta-estradiol. If the derivative is an ester, the derivative can beselected from mono- or di-esters since estradiol has hydroxy groups atthe 3- and 17-positions, the 3-mono and 17-mono as well as the 3,17di-esters can be made by generally known esterification methods. Someester derivatives will be absorbed more readily than the basic17-beta-estradiol. In selection of ester derivatives, it is ordinarilypreferred that the main estrogen hormone used be absorbed at a rate toprovide a desirable amount of the estrogen hormone component on a dailybasis in a system which simultaneously effects transdermal absorption ofthe progestin hormone in an effective daily dosage amount over a severalday period, preferably one week.

Regarding the daily dosages of progestin, about 100 to about 1500 mcg,preferably about 125 to about 250 mcg/day if the progestin used isnorgestimate and about 1000 mcg/day is generally satisfactory if theprogestin is norethindrone. Regarding estrogen, about 25 to about 50mcg/day of estrogen based on 17-beta-estradiol are presently believeddesired daily doses for humans.

Finally, the adhesive layer of the dosage unit is assembled with theother layer elements to form the dosage unit. The adhesive layerselected can vary depending on many factors including economic factorssuch as the type of manufacturing equipment most readily available, therapidity of absorption desired or other factors. For example, theadhesive layer can be applied directly to the polymer layer. A skinpermeation enhancer compound can be mixed thoroughly with the adhesivepolymer which is suitable for adhesion to the skin locus to which thetransdermal dosage unit will be applied. The progestin used is alsodissolved or microdispersed in the adhesive layer. The adhesive layercan be applied to the polymer layer by spraying or by solvent casting orlaminating. The concentration of skin permeation enhancer compound, ifemployed, can be reduced in the portion of the adhesive layer meanscoming in contact with the subject to be treated, especially if lessthan desired adhesion is realized in the adhesive layer, by applying thesurface portion of the adhesive layer separately, wherein the adhesivecomposition has a lower concentration of skin permeation enhancercompound or progestin or both. The adhesive layer is desirably thin inthe micron-range thickness, suitably 5-200 microns in thickness,desirably about 10 to 180 microns, and preferably about 20 to 150microns in thickness. Also, if desired, an additional adhesive means canbe used in the form of a ring adhered to the backing layer which extendsbeyond the circumference of the polymer layer.

The optional separating layer if empolyed is applied to the polymerlayer prior to the assembly of the adhesive layer (c) having presentprogestin. Alternatively, the separating layer can be applied to thesurface of the adhesive layer prior to its assembly into the dosageunit. The separating layer is suitably made of a suitablypolyisobutylene.

The absorption rate of one or both of the hormones of the transdermalhormone absorption dosage units of the invention can be increased, suchas by having an Enhancing Factor of at least 1.2, preferably at least1.3, and more preferably at least about 1.5 or 2.0. Enhancing Factor isdefined as the ratio of normalized permeation rate [in mcg/cm² /hr] of adosage unit of this invention with skin permeation enhancer/thenormalized permeation rate of a corresponding dosage unit withoutenhancer.

The invention also is a process for administering said hormonestransdermally by forming hormone-containing dosage units having apolymer layer which has the estrogen dosage dissolved or dispersedtherein, to which polymer layer is adhered a backing layer, said dosageunit having assembled therewith an adhesive layer, which transports theestrogen and progestin and contains the progestin and transdermalabsorption enhancing agent; applying the dosage unit in intimate contactwith the skin of the subject treated; and administering the hormonestransdermally to said subject to achieve fertility control or estrogenreplacement.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of a series of curves showing cumulative (Q)transdermal absorption of ethinyl estradiol from HAD TYPE TDDSH(adhesive type transdermal drug delivery system) through hairless mouseskin using seven different formulas.

FIG. 2 is a graph of a series of curves showing cumulative (Q)transdermal absorption of norethindrone from adhesive type transdermaldrug delivery system through hairless mouse skin using seven differentformulas.

FIG. 3 is a graph showing transdermal absorption rates of ethinylestradiol across human cadaver skin depending upon transdermalabsorption enhancer concentration.

FIG. 4 is a graph showing transdermal absorption rates of norethindroneacross human cadaver skin depending upon transdermal absorption enhancerconcentration.

FIG. 5 is a graph showing transdermal absorption ratio of ethinylestradiol through human cadaver skin from dosage units of the inventionin which both the polymer layer and adhesive layer are made fromadhesive polymer.

DETAILED DESCRIPTION OF THE INVENTION AND THE PREFERRED EMBODIMENTS

The backing layer can be made of any suitable material which isimpermeable to the hormones of the polymer layer. The backing layerserves as a protective cover for the polymer layer and provides also asupport function. The backing can be formed so that it is essentiallythe same size layer as the hormone-containing polymer layer or it can beof larger dimension so that it can extend beyond the side of the disclayer or overlay the side or sides of the hormone-containing disc layerand then can extend outwardly in a manner that the surface of theextension of the backing layer can be the base for an adhesive means.For long-term applications, e.g., for seven days, is desirable to usemicroporous and/or breathable backing laminates, so hydration ormaceration of the skin can be minimized. The adhesive means holds thedosage unit in intimate contact with the skin of the subject treated.Examples of materials suitable for making the backing layer are films ofhigh and polyvinylchloride, low density polyethylene, polypropylene,polyurethane, polyesters such as poly(ethylene phthalate), metal foils,metal foil laminates of such suitable polymer films, and the like.Preferably, the materials used for the backing layer are laminates ofsuch polymer films with a metal foil such as aluminum foil. In suchlaminates, a polymer film of the laminate will usually be in contactwith the polymer layer. The backing layer can be any appropriatethickness which will provide the desired protective and supportfunctions. A suitable thickness will be from about 10 to about 200microns. Desirably, the thickness will be from about 20 to about 150microns, and preferably be from about 30 to about 100 microns.

The polymer layer can also be made from polymer adhesives such aspolyacrylic, silicone or other suitable polymer adhesives. The polymerlayer can also be made, for example, from silicone elastomers of thegeneral polydimethylsiloxane structure, such as silicone polymers of thefollowing general formula: ##STR1## wherein R is alkyl or alkoxycontaining 1-7 carbon atoms, vinyl or phenyl and wherein n is about 100to about 5000.

The silicone polymers selected preferably are cross-linkable at moderatetemperatures, such as room temperature, using cross-linking catalystswhich are biologically acceptable in the final polymer layer and whichare compatible with the hormone components to be used in making thepolymer dosage forms. Various suitable crosslinking agents can be usedin crosslinking the above polymer, such as tetrapropoxy silane [Si(OCH₂CH₂ CH₃)₄ ], if the silicone polymer has free hydroxy groups such asterminal hydroxy groups. A tin catalyst can be used for suchcrosslinking reaction. If a silicone polymer component has vinyl groups,it can be crosslinked with a dimethyl-silicone polymer using a catalystsuch as a platinum catalyst. Some suitable silicone polymers arecross-linkable copolymers having dimethyl and methylvinyl siloxaneunits, which can be cross-linked as by using a suitable peroxidecatalyst. Other cross-linking sites can be present in the polysiloxaneelastomers used. Suitable silicone medical-grade polymers are sold underthe designations Silastic 382, Q7-4635, Q7-4650, Q7-4665, Q7-4735,Q7-4750, Q7-4765 and MDX-4-4210.

The silicone polymers selected can also have a "block" or "graft"structure or both. By "block" structure is meant that the polymer canhave a section or block of the polymer chain structure of the polymerwhich can have a repeating unit of one type, such as dimethylsiloxane,and then have a succeeding block made up of repeating units of anothertype, such as methylvinylsiloxane, diphenylsiloxane, diisopropylsiloxane units or other siloxane or silane units or even of monomerunits of a compatible non-siloxane or non-silane type. The blocks canvary in length and be repeated as desired. For example, if the blocksare represented as "A" and "B", respectively, the block copolymer can beA-B or A-B-A or A-B-A-B, etc. The "graft" structure simply means that tothe main polymer chain, one or more polymer chains are attached. Thosegrafted chains can have the same polymer units as those of the mainchain or can be different, as described above in connection with "block"copolymers. Also, the polymer used can be of a different type whereincopolymerizable monomers are placed together in a polymerization reactorso the main chain can have a certain population of each of the monomericunits.

The following are examples of block copolymers of the type which can beutilized in this invention. ##STR2## wherein x, y and z represent thenumber of repeating units sufficient to provide the desired property inthe polymer, such as from about 10 to about 5000.

Generally, those polymers used to form biologically acceptable polymerlayer are those capable of forming thin walls or coatings through whichhormones can pass at a controlled rate. Suitable polymers arebiologically and pharmaceutically compatible, non-allergenic andinsoluble in and compatible with body fluids or tissues with which thedevice is contacted. The use of soluble polymers is to be avoided sincedissolution or erosion of the matrix would affect the release rate ofthe hormones as well as the capability of the dosage unit to remain inplace for convenience of removal.

Exemplary materials for fabricating the biologically acceptable polymerlayer include polyethylene, polypropylene, polyurethane,ethylene/propylene copolymers, ethylene/ethylacrylate copolymers,ethylene/vinyl acetate copolymers, silicone elastomers, especially themedical-grade polydimethylsiloxanes, neoprene rubber, polyisobutylene,polyacrylate, chlorinated polyethylene, polyvinyl chloride, vinylchloride-vinyl acetate copolymer, polymethacrylate polymer (hydrogel),polyvinylidene chloride, poly(ethylene terephthalate), butyl rubber,epichlorohydrin rubbers, ethylene-vinyl alcohol copolymer,ethylene-vinyloxyethanol copolypolymer; silicone copolymers, forexample, polysiloxane-polycarbonate copolymers,polysiloxane-polyethylene oxide copolymers,polysiloxane-polymethacrylate copolymers, polysiloxane-alkylenecopolymers (e.g., polysiloxane-ethylene copolymers),polysiloxane-alkylenesilane copolymers (e.g.,polysiloxane-ethylenesilane copolymers), and the like; cellulosepolymers, for example methyl or ethyl cellulose, hydroxypropyl methylcellulose, and cellulose esters; polycarbonates;polytetrafluoroethylene; and the like. For best results, thebiologically acceptable polymer layer should be selected from polymerswith glass transition temperatures below room temperature. The polymermay, but need not necessarily, have a degree of crystallinity at roomtemperature. Cross-linking monomeric units or sites can be incorportedinto such polymers. For example, cross-linking monmers can beincorporated into polyacrylate polymers, which provide sites forcross-linking the polymer layer after microdispersing the hormones intothe polymer. Known cross-linking monomers for polyacrylate polymersinclude polymethacrylic esters of polyols such as butylene diacrylateand dimethacrylate, trimethylol propane trimethacrylate and the like.Other monomers which provide such sites include allyl acrylate, allylmethacrylate, diallyl maleate and the like.

The adhesive and polymer layers are suitable made using a siliconeadhesive, such as a (polydimethylsiloxane-silicate resin) copolymeradhesive depicted by the following formula: ##STR3## wherein Me ismethyl and R is --Si(CH₃)₃ and x and y represent independent numbers ofrepeating units sufficient to provide the desired properties in theadhesive polymer and other polymer layers.

For example, adhesive polymer products or amine-resistant adhesivepolymer products sold by Dow Corning, such as the ones sold under thedesignations of DC-355 and X7-2920 medical adhesives, are suitable foruse in making the adhesive layer. The adhesive polymer must bebiologically acceptable and compatible with the hormones and skinpermeation enhancer, if used. Certain polyacrylic adhesive polymers (inthe form of an alkyl ester, amide, free acid, or the like) orpolyisobutylene adhesive polymers can also be used with some hormones.Illustrative of suitable adhesive polymers for use in making the polymerlayer are shown by the following formulas: ##STR4## wherein x representsthe number of repeating units sufficient to provide the desiredproperties in the adhesive polymer and R is H or lower alkyl includingethyl, butyl and 2-ethylhexyl.

Other suitable hypoallergenic pressure-sensitive contact adhesivecompositions can also be used. A preferred adhesive layer ispressure-sensitive.

However, depending upon pharmaceutical compatibility and other factors,if desired, the adhesive means can be in the form of a ring attached,for example, to an extended portion of the backing layer so that theadhesive layer is adjacent to the sidewall of the hormone-containingdisc layer. The width of such adjacent adhesive ring must be adequate tohold the dosage unit securely to the subject being treated. Ordinarily,a suitable width of such adhesive ring can be about 0.2 to about 1.2 cm,preferably about 0.3 to about 1.0 cm.

The adhesive layer then is finally covered with a releasable protectivefilm layer which is made from materials which are substantiallyimpermeable to the hormones, the skin permeation enhancer, if used, andany other components of the dosage unit. The polymer materials and metalfoil laminates used for the backing layer may also be used to make theprotective layer, provided the layer is made strippable or releasablesuch as by applying conventional siliconizing or teflon coating. Asuitable releasable material for use with silicone polymer adhesiveDC-355 and X7-2970 is Scotchpak 1022 material sold by the 3M Company orBio-Release Material by Dow Corning.

In making the hormone-containing polymer layer, silicone elastomers,such as (polydimethylsiloxane-silicate resin) copolymer, polyacrylicadhesive, such as sold under the designation Duro-Tak, of the formuladescribed above, and other biocompatible adhesive polymers which providea stable environment for the hormones and permit their release, cansuitably be used. In making hormone-dispersed dosage units, it has beenfound suitable to use a dispersing agent, such as lactose and silica.Other suitable dispersing agents can also be used instead so long asthey are effective. Other suitable dispersing agents known to theformulating art can be used. Depending upon the hormones and the drugloading desired, a suitable amount of a dispersing agent can be variedfrom zero to about 20 percent (by weight) based on the weight of thepolymer layer. Commonly, the dispersing agent is added together with thehormone into the polymer used in making the layer. The amount ofdispersing agent added is dependent upon the rate of permeation desired,the particular hormones used, and at times, other factors. The amount ofthe hormones added depends upon the amount of hormone dosage and theduration of treatment desired in each dosage unit and the amount whichcan be incorporated into the polymer layer to retain suitablestructural, diffusion and other properties in the final polymer layer.It has been found, for example, that the hormones can be satisfactorilyadded to 50 parts of the polymer used in making the polymer layer, suchas polyacryic adhesive polymer. It has been found to be preferable toadd and disperse the estrogen used in an amount of a selected adhesivepolymer. The mixture of the polymer and hormones is then thoroughlymixed using a high-torque mixer to form a homogeneous solution ormicrodispersion of the hormones in the polymer. After the mixing step,the composition is subjected to vacuum to remove entrapped air.

The deaereated mixture is then applied as by solvent casting technique,to a suitable substrate, like backing laminate or release liner, andheated to a suitable elevated temperature to remove the solvent. Thetemperature used should not cause significant degradation of thehormones. The polymer sheet desirably is about 10 to 400 microns,preferably about 20 to about 300 microns, in thickness. The resultingmedicated polymer sheet is removed from the casting machine and anotherlayer of medicated polymer, containing the same or different hormone,can be further coated on the first medicated polymer layer formed bydirect casting or lamination.

The optional separating layer can be made of the adhesive or othermaterials described for use in making the adhesive layer havingprogestin present. In making the separating layer, it has been foundsuitable to use a bio-acceptable polyisobutylene having a suitablemolecular weight. For example, the poylisobutylene use can suitably havea relative molecular mass Mv (viscosity average) of from about 800,000to about 900,000, such as that of polyisobutylene sold by BASF under thedesignation Oppanol B80, which has a relative molecular mass Mv(viscosity average) value of 850,000. The viscosity average relativemolecular mass is obtained from the equation: J_(o) =3.06×10⁻² ×M 0.65.The viscosity or molecular weight should, generally speaking, beselected which is sufficiently high to provide a separating layer whichis dimensionally stable and which is not excessively high so as to makefabrication of the separating layer unnecessarily difficult to provide afunctional and pharmaceutically elegant dosage unti.

The thickness of the separating layer can vary as desired. However, ithas been found that a layer thickness after any solvent removal of about50 to about 150 microns to be suitable, with a thickness of about 75 to125 microns to be preferable. It has been found that a separating layerhaving about 100 micron thickness made of a polyisobutylene having aviscosity or molecular weight such as that of Oppanol B80 to functionwell, if the estrogen in the polymer layer is 17-beta-estradiol orethinyl estradiol.

The separating layer should have sufficient thickness to minimize anymigration, especially under prolonged storage conditions at elevatedtemperatures, such as 37° C. or 45° C. or greater. Also, the separatinglayer should be made of a suitable material and with a sufficientthickness to decelerate the rate of transmission of the estrogen in thepolymer layer, as needed to provide suitably a delivery ratio oftransdermal absorption from 10-30/l , a ratio of about 12 to about 20being a preferable ratio range.

It has been found that the separating layer can be made as by dissolvingabout 10 parts of a suitable polyisobutylene, such as Oppanol B80polyisobutylene in a suitable solvent, such a a mixture of cyclohexane,hexane and heptane (for example, a 1:1:1 mixture). The mixture is gentlyagitated such as by using a suitable rotator.

When the dissolution is substantially complete to provide a clearpolyisobutylene solution, the solution can be used to coat a lowadhesion film, such as a polyester film with a fluoropolymer-coatedsurface such as the material sold by 3M Company under the designationScotch-Pak 1022. A R.D. wireless coating bar (such as a #12) can be usedfor coating. The resulting coating is dried and is repeated as necessaryto obtain a layer of desired thickness, such as 100 microns. Theseparating layer thus formed can be assembled into the dosage unit bylamination to the polymer layer. Alternatively, the separating layer canbe applied to the upper surface of the adhesive layer having presentprogestin before being assembled by lamination to the lower surface ofthe polymer layer having present estrogen. The finished multilayeredpolymer layer can then be cut to form discs with desired shapes andsizes. The polymer layer disc generally should not exceed about 100 sq.cm in area, suitably about 5 to 100 sq. cm, preferably, about 8 to about80 sq. cm, generally about 10 to 60 sq. cm being more preferable. Theshape of the layer discs can vary; they can be circular, square,rectangular or other desired shape.

The hormone-containing polymer layer, generally speaking, may containsome excess of the dispersed hormone over the dosage amount desired tobe transdermally absorbed by the subject to be treated. Ordinarily, thisexcess is small, such as less than 2-fold excess over a weekly projecteddose, depending upon the physiochemical properties of the hormones, aswell as the nature of the polymer in the polymer layer disc and otherfactors.

The adhesive means, if it contains a skin permeation enhancer, is madeas by dissolving the enhancer and the progestin directly in the adhesivepolymer solution or in a solvent which is compatible with the adhesivepolymer solution used to make the adhesive layer containing the skinpermeation enhancer. Any suitable amount of solvent can be used asnecessary to dissolve the quantity of enhancer and progestin to beadmixed with the adhesive polymer solution used. For example, 3 to 10parts of solvent can be used to dissolve one part of skin permeationenhancer, depending upon the solubility of the enhancer. When usingpolydimethylsiloxane adhesive solution, it has been found suitable touse 2 to 20 parts of skin permeation enhancer in 20 to 50 parts ofsolvent (such as acetone, methyl ethyl ketone, trifluorotrichloroethaneor other suitable solvent) and add the solution to 100 parts of theadhesive solution. The enhancer-adhesive combination is throughly mixedand a coating thereof is applied using a film coating machine, such asreferred to in the art as a K-bar coater, directly onto the polymerlayer or to a strippable release liner before laminating onto thepolymer layer, as described above. A suitable release liner is apoly(ethylene phthalate) laminated with aluminum foil or a Teflon-coatedpolyester film such as sold under the designation Scotchpak 1022 orBio-release X7-2741 or X7-2752. The poly(ethylene phthalate) side towhich the adhesive-enhancer-progestin coating is applied, is madestrippable by conventional siliconizing or by other suitable means. Thethickness of the adhesive-enhancer-progestin layer normally is suitableabout 20 to about 200 microns, preferably about 30 to about 150 microns.

The amount of enhancer in the adhesive layer depends in part on therapidity at which it is desired that the hormones be absorbed. Generallyspeaking, about 1 to about 30 percent of skin permeation enhancer basedon the weight of the adhesive is suitable, depending upon the enhancer,adhesive polymer, desired adhesiveness and other factors. Desirably,about 5 to about 20 percent of skin permeation enhancers are useddepending upon the above recited factors. The adhesive layer containingthe progestin and skin permeation enhancer is transferred to the polymerlayer disc surfaces by application of lamination technique under aconstant pressure. In order to assure adequate adhesion of the adhesivepolymer layer to the skin of the subject treated, additional adhesivepolymer coating having a relatively low concentration of enhancer, e.g.,1-5 percent based on the weight of the adhesive polymer can be furtherapplied to the surface of progestin-enhancer-polymer layer. Thethickness of this coating ordinarily is a minor percentage of thethickness of the final adhesive layer, such as 20-40 percent of thetotal adhesive polymer layer. In the progestin-containing adhesive layerhaving a suitable higher concentration of the enhancer is used. Suitablehigher concentrations of enhancer are usually 10 to about 30 percentbased on the adhesive polymer weight, the solubility and desired finalamount of skin enhancer agent and other factors. The solvent of therespective coatings is removed by evaporation. The respective coatingscan be combined to make the final multilayered fertility-controltransdermal dosage form by application of lamination technique under aconstant pressure or sequential solvent casting technique.

The multi-layer transdermal hormone dosage units are excised. Thebacking layer, if desired, can be shaped around the sides of the dosageunit, including the polymer layer, if such protection is desired. Theresulting hormone polymer dosage unit forms are then placed inappropriate packaging for storage until they are to be applied intransdermal treatment.

At least one estrogen and at least one progestin as defined above aredissolved and/or microdispersed in the polymer and adhesive layers,respectively. With the controlled release of the hormones at arelatively steady rate over a prolonged period, typically several daysand preferably one week, the subject is provided with the benefit of asteady infusion of the hormones over a prolonged period.

One of the presently preferred estrogens is 17-beta-estradiol. It is anatural hormone and ordinarily transdermally delivered by an adaptablesystem of this invention at a desirable daily rate. The17-beta-estradiol is compatible and can be dissolved or microdispersedin the polymer. The transdermal dosage unit designed for one-weektherapy is required to deliver at least about 100 to about 500 mcg(preferably about 125 to about 250 mcg)/day of norgestimate or about1000 mcg/day of norethindrone and 20-50 mcg/20 cm² /day of17-beta-estradiol (or an equivalent effective amount of ethinylestradiol or another estrogen). In fertility control, that amount ofprogestin is believed to be necessary to inhibit ovulation and thatamount of estrogen is believed needed to maintain normal femalephysiology and characteristics. Derivatives of 17-beta-estradiol whichare biocompatible, capable of being absorbed transdermally andpreferably bioconvertible to 17-beta-estradiol can also be used, if theamount of absorption meets the required daily dose of the estrogencomponent and if the hormone components are compatible. Such derivativesof estradiol can be selected from esters, either mono- or di-esters. Themono-esters can be either 3- or 17-esters. The estradiol esters can be,illustratively speaking, estradiol-3,17-diacetate; estradiol-3-acetate;estradiol-17-acetate; estradiol-3,17-divalerate; estradiol-3-valerate;estradiol-17-valerate; 3-mono, 17-mono and 3,17-dipivilate esters;3-mono, 17-mono and 3,17-dipropionate esters; corresponding cypionate,heptanoate, benzoate and the like esters; ethinyl estradiol; estrone;and other estrogenic steroids and derivatives thereof which aretransdermally absorbable, including benzestrol, chlorotrianisene,dienestrol, mestranol, and the like.

The progestin can be and presently preferably is norethindrone ornorgestimate or combinations thereof. However, other suitable progestinscan be used in place thereof or in combination therewith. For example, aprogestin can be selected from levonorgestrel, norethynodrel,dydrogesterone, ethynodiol acetate, hydroxyprogesterone caproate,medroxyprogesterone diacetate, norethindrone acetate, norgestrel,progesterone, and the like.

It will be suggested to those skilled in the art to use other estrogensor progestins in forming the dosage units of this invention. Such use ofother estrogens and progestins are intended to be within the scope ofthis invention insofar as use thereof provides satisfactory dosage unitswithin the spirit of this invention.

The skin permeation enhancers which can be used in carrying out thisinvention can vary. Ones that give preferred results with the polymerdosage unit form having a specific hormone can vary. In some instances,the use of permeation enhancer in making a dosage unit will result ingood or even excellent absorption for one hormone, may result in no orrelatively low enhancement when another hormone is used. Use ofcombinations of two or more of the skin permeation enhancer compoundsfrequently result in superior results, such as greater transdermalabsorption.

Specific skin permeation enhancers which can be used in making thepolymer dosage forms of this invention include saturated and unsaturatedfatty acids and their esters, alcohols, monoglycerides, acetate,diethanolamides and N, N-dimethylamides, such as oleic acid, propyloleate, oleyl acetate, propyl myristate, isopropyl myristate, myristylalcohol, myristyl N, N-dimethyl amide, stearic acid and stearyl alcohol,stearyl propyl ester, monostearin, and combinations of them with, forexample, 1-dodecylazacycloheptan-2-one sold under the trademark Azone byNelson Research and Development; decyl methyl sulfoxide, dimethylsulfoxide, salicylic acid and derivatives, N,N-diethyl-m-toluamide,crotamiton, 1-substituted azacycloalkan-2-ones such as disclosed in U.S.Pat. No. 4,316,893 (the 1-substituent having 0-17 carbon atoms,preferably, 1-11 carbon atoms), and various other compounds which arebiologically compatible and have transdermal permeation enhancementactivity. It has been found that n-decyl alcohol is a preferredenhancing agent. Also, it has been found that capric acid is a preferredenhancing agent. Modifications will be suggested to those skilled in theart to the chemical structures represented by n-decyl alcohol or capricacid which do not detract substantially from their function as preferredenhancing agent. It has been found that about 10 to about 40 percent(W/W) of n-decyl alcohol or capric acid is ordinarily a suitable amount.It has been found that about 20 to about 35 percent (W/W) in theadhesive layer of these enhancing agents provide highly satisfactoryskin absorption enhancement and satisfactory adhesion. Amounts higherthan 35 or 40 percent (W/W) can diminish skin absorption enhancement andinterfere with satisfactory adhesion to the subject being treated.

Ethyl alcohol and other short chain alkanols (with 1-4 carbon atoms)which have substantially the same properties and activity as ethylalcohol do not come within the definition of skin permeation enhancer asused herein.

The following examples are in illustration of the invention and are notintended to be limiting.

EXAMPLE 1

The following ingredients are used in making the estrogen-containingpolymer layer: ethinyl estradiol, 5 parts; polyacrylic adhesive sold byNational Starch and Chemical Corp. as Duro-Tak 80-1054, 100 parts.

The ethinyl estradiol is added to the polyacrylic adhesive using a hightorque mixer (sold by Cole-Parmer Company) at a rate of about 1000 RPM.

The hormone mixture is applied to the backing layer formed ofpolyester/aluminum laminate sold by 3M Company as Scotch-Pak 1005, byusing a K-bar coater equipped with a number 3 bar. The resulting polymerlayer is dried in the hood for one hour to remove the solvents. Thethickness of the polymer layer obtained is about 10 microns.

To the polymer layer, a 5% (W/W) norethindrone in polyacrylic adhesivesolution is applied using a K-bar coater (with #16 bar). In addition tonorethindrone, this coating solution also contains 25% (W/W) of n-decylalcohol as skin permeation enhancer. The coating is dried at ambientroom temperature for 24 hours. The dried norethindrone-reservoiradhesive layer has a dry thickness of about 120 microns.

The bilayer dosage units are then covered with a transparentlow-adhesion release liner (Scotch-Pak 1022/3M). The completed dosagelayers are then cut into dosage units having various shapes and sizes byusing a specially-designed device cutter, such as a 20 cm² rectangularshape.

The transdermal absorption of the hormones from the anti-fertilitypolymer dosage units of this invention is evaluated by using a skinspecimen from a "hairless" mouse or human cadaver by following theprocedure described by Y. W. Chien, K. Valia and U. B. Doshi in DrugDevelop. & Ind. Pharm., 11(7) 1195-1212 (1985).

Transdermal polymer dosage units are obtained following generally theprocedures described above and evaluated as shown in the followingTables 1-3.

                  TABLE 1                                                         ______________________________________                                        Rates of Permeation.sup.1 for Ethinyl Estradiol                               and Norethindrone Across Hairless Mouse Skin.sup.2                                              Permeation Rate                                                               (mcg/cm.sup.2 /hr ± S.D.)                                                                 (n = 3)                                      Formulation                                                                            Enhancer Ethinyl Estradiol.sup.3                                                                      Norethindrone.sup.4                          ______________________________________                                        1        none     0.04 (± 0.01)                                                                             0.45 (± 0.07)                             2        IPM      0.25 (± 0.05)                                                                             0.97 (± 0.19)                             3        DMSO     0.13 (± 0.02)                                                                             0.52 (± 0.14)                             4        DeMS     0.16 (± 0.03)                                                                             0.39 (± 0.07)                             5        LA       0.19 (± 0.03)                                                                             0.76 (± 0.20)                             6        OA       0.26 (± 0.04)                                                                             1.21 (± 0.22)                             7        DeA      0.30 (± 0.06)                                                                             2 51 (± 0.49)                             8        CA       0.25 (± 0.04)                                                                             2.04 (± 0.30)                             ______________________________________                                         .sup.1 12 samples were taken during 115 hours of study.                       .sup.2 Sevenweek-old female hairless mouse abdominal skin.                    .sup.3 Loading dose: 30.5 (± 1.3) mcg/cm.sup.2                             .sup.4 Loading dose: 338.0 (± 10.1) mcg/cm.sup.2                           IPM (isopropyl myristate); DMSO (dimethyl sulfoxide); DeMS (decyl methyl      sulfoxide); LA (lauric acid); OA (oleic acid);                           

                  TABLE 2                                                         ______________________________________                                        Rates of Permeation.sup.1 for Ethinyl Estradiol                               and Northindrone Across Human Cadaver Skin.sup.2                                                Permeation Rate                                                               (mcg/cm.sup.2 /hr ± S.D.)                                                                 (n = 3)                                      Formulation                                                                            Enhancer Ethinyl Estradiol.sup.3                                                                      Norethindore.sup.4                           ______________________________________                                        1        none     0.02 (± 0.004)                                                                            0.14 (± 0.03)                             2        IPM      0.09 (± 0.02)                                                                             0.39 (± 0.07)                             3        DMSO     0.04 (± 0.01)                                                                             0.17 (± 0.03)                             4        DeMS     0.05 (± 0.01)                                                                             0.12 (± 0.02)                             5        LA       0.07 (± 0.02)                                                                             0.26 (± 0.04)                             6        OA       0.09 (± 0.02)                                                                             0.46 (± 0.09)                             7        DeA      0.13 (± 0.02)                                                                             0.89 (± 0.18)                             8        CA       0.07 (± 0.01)                                                                             0.80 (± 0.14)                             ______________________________________                                         .sup.1 12 samples were taken during 122 hours of study.                       .sup.2 A 17year-old black boy's left anterial leg with average thickness      of 220 (± 26) microns.                                                     .sup.3 Loading dose: 30.5 (±1.3) mcg/cm.sup.2.                             .sup.4 Loading dose: 338.0 (± 10.1) mcg/cm.sup.2.                     

                  TABLE 3                                                         ______________________________________                                        Enhancing Effect of Skin Permeation Enhancer on the Skin                      Permeation Rates.sup.1 of Ethinyl Estradiol and Norethindrone                 Across Human Cadaver Skin.sup.2                                                                 Permeation Rate                                                               (mcg/cm.sup.2 /hr ± S.D.)                                                                 (n = 3)                                      Formulation                                                                            Enhancer Ethinyl Estradiol.sup.3                                                                      Norethindrone.sup.4                          ______________________________________                                        n-Decyl Alcohol (% w/w)                                                        9       0        0.13 (± 0.02)                                                                             0.10 (± 0.02)                             10       2.5      0.15 (± 0.03)                                                                             0.09 (± 0.02)                             11       5.0      0.36 (± 0.06)                                                                             0.17 (± 0.03)                             12       10.0     0.48 (± 0.07)                                                                             0.25 (± 0.04)                             13       25.0     1.28 (± 0.19)                                                                             1.24 (± 0.18)                             14       50.0     1.06 (± 0.18)                                                                             1.45 (± 0.21)                             Capric acid (% w/w)                                                           15       1.0      0.12 (± 0.02)                                                                             0.08 (± 0.01)                             16       2.5      0.13 (± 0.02)                                                                             0.08 (± 0.01)                             17       5.0      0.19 (± 0.03)                                                                             0.13 (± 0.02)                             18       10.0     0.26 (± 0.04)                                                                             0.23 (± 0.04)                             19       25.0     0.39 (± 0.07)                                                                             0.33 (± 0.05)                             20       50.0     0.40 (±  0.06)                                                                            0.49 (± 0.10)                             ______________________________________                                         .sup.1 13 samples were taken during 168 hours of study period.                .sup.2 A white male's anterial trunk with average thickness of 180 ± 2     microns (n = 6) were used.                                                    .sup.3 Loading dose: 95.7 (± 2.9) mcg/cm.sup.2                             .sup.4 Loading dose: 1.26 (± 0.03) mg/cm.sup.2                        

EXAMPLE 2

The formulations of the above Tables are repeated using the followingprocedure.

The following ingredients are used in making the estrogen-containingpolymer layer: ethinyl estradiol, 5 parts; polyacrylic adhesive sold byNational Starch and Chemical Corp. as Duro-Tak 80-1054, 100 parts.

The ethinyl estradiol is added to the polyacrylic adhesive using a hightorque mixer (sold by Cole-Parker Company) at a rate of about 1000 RPM.

The hormone mixture is applied to the backing layer formed ofpolyester/aluminum laminate sold by 3M Company as Scotch-Pak 1005, byusing a K-bar counter equipped with a number 3 bar. The resultingpolymer layer is dried in the hood for one hour to remove the solvents.The thickness of the polymer layer obtained is about 10 microns.

To the polymer layer, a 5% (W/W) norethindrone in polyacrylic adhesivesolution is applied on a transparent low-adhesion substrate using aK-bar coater (with #16 bar). In addition to norethindrone, this coatingsolution also contains 25% (W/W) of n-decyl alcohol as skin permeationenhancer. The coating is dried in the hood at ambient room temperaturefor 24 hours. The dried norethindrone-reservoir adhesive layer has athickness of about 120 microns.

The norethindrone layer is carefully applied to the ethinyl estradiollayer by lamination technique. The completed dosage layers are then cutinto dosage units having various shapes and sizes by using aspecially-designed device cutter, such as 20 cm² rectangular shape.

EXAMPLE 3

Example 1 is repeated except the ethinyl estradiol loading in thepolymer layer is varied from 200 mcg/20 cm² to 1600 mcg/20 cm². Theabove formulation 13 is used. The data show that the rate of permeationacross human skin increases as the loading of ethinyl estradiolincreases until the loading concentration reaches about 1600 mcg/20 cm²,at which point increased loadings according to the data of theexperiment do not provide increased permeability. This is shown in thechart of FIG. 5.

EXAMPLE 4

Examples 1 and 2 are repeated except bioactively equivalent amounts of17-beta-estradiol are used instead of ethinyl estradiol.

EXAMPLE 5

Examples 1 and 2 are repeated except bioactively equivalent amounts ofnorgestimate are used instead of norethindrone.

EXAMPLE 6

Examples 1 and 2 are repeated except bioactively equivalent amounts of17-beta-estradiol and norgestimate are used instead of ethinyl estradioland norethindrone, respectively.

EXAMPLE 7

Examples 1, 2, 4, 5 and 6 are repeated using polydimethylsiloxaneadhesive instead of the polyacrylic adhesive.

EXAMPLE 8

The following ingredients are used in making a trilayer transdermalestrogen/progestin dosage unit:

(I) Ethinyl estradiol, 1 part; polyacrylic adhesive (sold by NationalStarch and Chemical Corp., as Duro-Tak 80-1054), 99 parts. The ethinylestradiol is dissolved in the polyacrylic adhesive by gently rotatingthe container using rotator (Cole-Parmer Company) at low speed (10 rpm)to form a clear solution. This hormone/adhesive mixture is applied bycoating to a sheet of polyester/aluminum laminate (sold by 3M Company asScotch-Pak 1109), on the polyester surface, using a R.D.wireless-coating bar (#8). The resulting polymer layer is dried in thehood for one hour to remove the solvent portion. The thickness of thedried estrogen reservoir polymer adhesive layer obtained is about 40microns.

(II) Polyisobutylene polymer (sold by BASF, as Oppanol B80), 10 parts;1:1:1 mixture of cyclohexane/hexane/heptane as solvent system forOppanol B80, 90 parts. The polyisobutylene polymer is dissolved in thesolvent system in a closed container by gently rotating the containerusing a rotator (Cole-Palmer Company) at low speed (10 rpm) until allthe polymer is dissolved and a clear solution is formed. This polymersolution is applied to the low-adhesion side of a substrate (a polyesterfilm with fluoropolymer-coated surface, sold by 3M Company as Scotch-Pak1022) using R.D. wireless coating bar (#12). This polymer coating isdried in the hood for 2 hours. The resulting dried polymer film has athickness of about 100 microns.

(III) Norethindrone, 5 parts; n-decyl alcohol, 35 parts; polyacrylicadhesive (sold by National Starch and Chemical Corp. as Duro-Tak80-1054), 60 parts. The norethindrone is dispersed in n-decyl alcohol byrotating gently the container using a rotator (Cole-Palmer Company) atlow speed (10 rpm) to form a drug suspension. The polyacrylic adhesiveis then added to the suspension and the mixture is rotated gently againusing the same rotator at a speed of 10 rpm until a homogeneous mixtureis obtained. The mixture is applied to the low-adhesion side of asubstrate (a polyester with fluoropolymer-coated surface, sold by 3MCompany as Scotch-Pak 1022) using a R.D. wireless coating bar (#28).This coating layer is dried in the hood for 24 hours. The thickness ofthe dried norethindrone/n-decyl alcohol reservoir layer obtained isabout 250 microns.

The polyisobutylene product of (II) is laminated onto the product of (I)containing ethinyl estradiol. The layer of (III) containingnorethindrone is then laminated into the combined laminates (I) and(II), on the surface of layer (II), to form the final product. The finallaminated product is cut into specific size using steel die cutter toform the tri-layer transdermal estrogen/progestin dosage unit.

Units of 10 sq cm are individually packed in the paper/foil/polyesterpouches which are then thermally sealed by a thermal sealer. Thesesealed pouches are stored in the stability testing cabinets (GravityConvection Incubator, sold by GCA Corp.) at three differenttemperatures, room temperature, 37° C. and 45° C. for up to 26 weeks.During the storage, pouches are randomly sampled at specific intervals,according to the sampling schedule shown in Table 4. The units sealed inthe pouches are evaluated for their drug content and skin permeationrate profiles. Drug content in each unit was determined by a solventextraction procedure followed by a high performance liquid chromatograph(HPLC) of the drugs. The skin permeation rate profiles of drugs releasedfrom the unit were determined by a hydrodynamically well-calibratedin-vitro skin permeation cell system. The skin specimen freshly excisedfrom 5-to-7 week old female hairless mouse skin was used as the modelskin. The skin permeation study was performed at 37° C. using 40% V/VPEG 400 saline solution as receptor solution. The steady-state skinpermeation rate of norethindrone and ethinyl estradiol was determinedfrom the slope of a Q vs time plot, where Q is the cumulative amount ofdrug permeating through the skin at a specific sampling time interval.It was calculated by determining the drug concentration in the receptorsolution by the HPLC assay.

Drug content or skin permeation rate of drug determined from thestability samples were plotted, according to storage temperature,against the storage time. A 95% confidence limit, based on the meanvalue obtained from the week 0 samples, is established to makestatistical judgment on the physical and chemical stability of the unittested. Data point that falls outside the 95% confidence limit lines isconsidered as either chemically (from drug recovery study) or physically(from skin permeation study) unstable.

                  TABLE 4                                                         ______________________________________                                        Temperature                                                                              Sampling Schedule (Weeks)                                          (° C.)                                                                            0       1     2     4   8     12  26                               ______________________________________                                        Room       X       --    --    X   X     X   X                                37         X       --    X     X   X     X   X                                45         X       X     X     X   X     X   X                                ______________________________________                                    

                                      TABLE 5                                     __________________________________________________________________________    Drug Recovery Data of Stability Samples of Dosage Units of Example 8                 Sampling Time (Weeks After Storage)                                    Temperature                                                                          0    1   2   4   8   12   26                                           __________________________________________________________________________    Ethinyl Estradiol (mcg/10 cm.sup.2 ± S.D.).sup.(1,2)                        Room Temp.                                                                          529.7                                                                              --  --  514.5                                                                             527.7                                                                             517.6                                                                              511.1                                               (32.98)      (35.57)                                                                           (34.99)                                                                           (27.89)                                                                            (31.31)                                      37° C.)                                                                       552.2                                                                              --  576.8                                                                             539.5                                                                             531.1                                                                             538.9                                                                              522.1                                               (33.89)  (37.22)                                                                           36.67)                                                                            (29.45)                                                                           (43.41)                                                                            (29.82)                                      45° C.                                                                        540.4                                                                              530.7                                                                             522.7                                                                             539.6                                                                             513.6                                                                             505.7                                                                              495.2                                               (33.71)                                                                            (39.98)                                                                           (37.11)                                                                           (29.67)                                                                           (29.98)                                                                           (42.11)                                                                            (34.72)                                      Norethindrone (mcg/10 cm.sup.2 ± S.D.).sup.(1,2)                            Room Temp.                                                                          14.18                                                                              --  --  13.43                                                                             13.11                                                                             14.14                                                                              13.01                                               (0.98)       (1.06)                                                                            (1.18)                                                                            (1.32)                                                                             (1.24)                                       37° C.                                                                        16.67                                                                              --  15.57                                                                             15.11                                                                             14.40                                                                             14.11                                                                              13.79                                               (1.09)   (1.41)                                                                            (1.11)                                                                            (1.61)                                                                            (1.24)                                                                             (1.18)                                       45° C.                                                                        15.22                                                                              15.01                                                                             14.77                                                                             14.78                                                                             13.49                                                                             13.29                                                                              13.77                                               (1.43)                                                                             (1.14)                                                                            (1.02)                                                                            (1.31)                                                                            (1.29)                                                                            (1.08)                                                                             (1.19)                                       __________________________________________________________________________     .sup.(1) Mean ±  Standard Deviation (N = 3)                                .sup.(2) Triplicate sample dosage units solvent extracted at indicated        storage times and temperatures and the ethinyl estradiol and norethindron     contents determined using high performance liquid chromatography (HPLC). 

                                      TABLE 6                                     __________________________________________________________________________    Skin Permeation Rate of Stability Samples of Dosage Units of Example 8               Sampling Time (Weeks After Storage)                                    Temperature                                                                          0    1   2   4   8   12   26                                           __________________________________________________________________________    Ethinyl Estradiol (mcg/10 cm.sup.2 hr ± S.D.).sup.(1,2)                     Room Temp.                                                                          0.20 --  --  0.26                                                                              0.19                                                                              0.26 0.22                                                (0.034)      (0.033)                                                                           (0.021)                                                                           (0.033)                                                                            (0.021)                                      37° C.                                                                        0.25 --  0.27                                                                              0.22                                                                              0.29                                                                              0.30 0.22                                                (0.027)  (0.040)                                                                           (0.018)                                                                           (0.027)                                                                           (0.041)                                                                            (0.031)                                      45° C.                                                                        0.28 0.25                                                                              0.21                                                                              0.31                                                                              0.22                                                                              0.23 0.20                                                (0.041)                                                                            (0.022)                                                                           (0.026)                                                                           (0.039)                                                                           (0.033)                                                                           (0.042)                                                                            (0.031)                                      Norethindrone (mcg/10 cm.sup.2 ± S.D.).sup.(1,2)                            Room Temp.                                                                          2.46 --  --  2.38                                                                              2.09                                                                              2.15 2.57                                                (0.26)       (0.31)                                                                            (0.19)                                                                            (0.25)                                                                             (0.35)                                       37° C.                                                                        2.33 --  2.46                                                                              2.37                                                                              2.72                                                                              2.44 2.21                                                (0.31)   (0.41)                                                                            (0.35)                                                                            (0.41)                                                                            (0.39)                                                                             (0.34)                                       45° C.                                                                        2.29 2.56                                                                              2.33                                                                              2.71                                                                              2.53                                                                              2.56 2.28                                                (0.33)                                                                             (0.37)                                                                            (0.28)                                                                            (0.37)                                                                            (0.37)                                                                            (0.35)                                                                             (0.31)                                       __________________________________________________________________________     .sup.(1) Mean ± Standard Deviation (N = 3)                                 .sup.(2) Permeation rates of triplicate sample dosage units determined        using 5-7 week old female hairless mouse skin in Chien et al. procedure       for 146 hours and the rates determined from slope of Q vs permeation time     plots.                                                                   

                  TABLE 7                                                         ______________________________________                                        Effect of Thickness of Polyisobutylene Layer (Oppanol B80)                    on Permeation Rates Across Human Cadaver Skin                                            Human Cadaver Skin Permeation Rates.sup.a,b,c,d                    Formulation                                                                              (mcg/sq cm hr ± S.D.)                                           Number     Ethinyl Estradiol                                                                            Norethindrone                                       ______________________________________                                         2-0       0.22 (0.041)   1.15 (0.100)                                        2-1        0.24 (0.033)   1.03 (0.170)                                        2-2        0.20 (0.021)   1.24 (0.210)                                        2-3        0.16 (0.029)   0.97 (0.160)                                        2-4        0.16 (0.031)   1.19 (0.240)                                        2-5        0.14 (0.021)   1.04 (0.250)                                        2-6        0.09 (0.017)   1.26 (0.280)                                        2-7        0.06 (0.014)   1.06 (0.190)                                        2-8        0.04 (0.010)   1.17 (0.200)                                        2-9        0.02 (0.006)   1.06 (0.230)                                        ______________________________________                                         .sup.a 11 samples were taken for each of the triplicate experiments (n =      3) during 146 hours of study.                                                 .sup.b 40% PEG 400/saline was used as receptor solution.                      .sup.c Anterior trunk of a young caucasian female cadaver skin was used.      .sup.d Procedure of Chien et al. used, samples taken at times 0, 2, 4, 8,     12, 24, 48, 72, 96, 120, and 146, and rates determined from slopes of Q v     permeation time plots.                                                   

                  TABLE 8                                                         ______________________________________                                        Variation of Permeation Rates of Norethindrone                                Depending on Content of Enhancer                                                                       Norethindrone                                        Formulation                                                                             % (W/W) of n-Decyl                                                                           Skin Permeation Rate.sup.1,2                         Number    Alcohol        (mcg/sq cm hr ± S.D.)                             ______________________________________                                        2-10      0              0.13 (± 0.02)                                     2-11      10             0.31 (± 0.07)                                     2-12      20             0.49 (± 0.06)                                     2-13      30             0.87 (± 0.17)                                     2-7       35             1.10 (± 0.24)                                     2-14      40             1.17 (± 0.21)                                     2-15      45             1.23 (± 0.29)                                     ______________________________________                                         .sup.1 11 samples were taken for each of triplicate experiments (n = 3)       during 146 hours of study.                                                    .sup.2 Procedure of Chien et a1. used, samples taken at times 0, 2, 4, 8,     12, 24, 48, 72, 96, 120, and 146, and rates determined from slopes of Q v     permeation time plots.                                                   

                  TABLE 9                                                         ______________________________________                                        Variation of Permeation Rate Ratios                                           Depending on Enhancer Contents                                                                         Ratio of Permeation                                                           Rates                                                Formulation                                                                             % (W/W) of n-Decyl                                                                           Norethindrone/Ethinyl                                Number    Alcohol        Estradiol                                            ______________________________________                                        2-10      0               4.19 (± 0.41)                                    2-11      10              8.38 (± 0.77)                                    2-12      20             12.56 (± 1.49)                                    2-13      30             18.13 (± 2.33)                                    2-7       35             18.33 (± 2.74)                                    2-14      40             15.39 (± 1.96)                                    2-15      45             13.98 (± 1.87)                                    ______________________________________                                    

                  TABLE 10                                                        ______________________________________                                        Variation of Permeation Rates of Norethindrone                                Depending on Content of Enhancer                                                                     Norethindrone                                          Formulation % (W/W) of Skin Permeation Rate.sup.1,2                           Number      Capric Acid                                                                              (mcg/sq cm hr ± S.D.)                               ______________________________________                                        2-10        0          0.13 (± 0.02)                                       2-16        10         0.41 (± 0.07)                                       2-17        20         0.66 (± 0.11)                                       2-18        30         1.16 (± 0.19)                                       2-19        35         1.48 (± 0.24)                                       2-20        40         1.59 (± 0.34)                                       2-21        45         1.84 (± 0.15)                                       ______________________________________                                         .sup.1 11 samples were taken for each of triplicate experiments. (n = 3)      during 146 hours of study.                                                    .sup.2 Procedure of Chien et al. used, samples taken at times 0, 2, 4, 8,     12, 24, 48, 72, 96, 120 and 146, and rates determined from slopes of Q vs     permeation time plots.                                                   

                  TABLE 11                                                        ______________________________________                                        Variation of Permeation Ratios                                                Depending on Enhancer Contents                                                                         Ratio of Permeation                                                           Rates                                                Formulation                                                                             % (W/W) of Capric                                                                            Norethindrone/Ethinyl                                Number    Acid           Estradiol                                            ______________________________________                                        2-10      0               4.19 (± 0.41)                                    2-16      10             12.42 (± 1.96)                                    2-17      20             14.04 (± 2.11)                                    2-18      30             15.68 (± 1.91)                                    2-19      35             15.91 (± 1.77)                                    2-20      40             12.82 (± 2.01)                                    2-21      45             12.35 (± 1.44)                                    ______________________________________                                    

                  TABLE 12                                                        ______________________________________                                        Variation of Permeation Rates of Ethinyl Estradiol                            Depending on Thickness of Adhesive Layer                                                 Thickness of                                                                              Ethinyl Estradiol                                      Formulation                                                                              Adhesive Layer                                                                            Skin Permeation Rate.sup.1,2                           Number     (Microns)   (mcg/sq cm hr ± S.D.)                               ______________________________________                                        2-22       142.8       0.079 (± 0.009)                                     2-23       178.5       0.070 (± 0.010)                                     2-24       214.2       0.066 (± 0.008)                                     2-7        250.0       0.060 (± 0.011)                                     2-25       285.6       0.066 (± 0.015)                                     2-26       321.7       0.074 (± 0.011)                                     ______________________________________                                         .sup.1 11 samples were taken for each of triplicate experiments (n = 3)       during 146 hours of study.                                                    .sup.2 Procedure of Chien et al. used, samples taken at times 0, 2, 4, 8,     12, 24, 48, 72, 96, 120 and 146, and rates determined from slopes of Q vs     permeation time plots.                                                   

                  TABLE 13                                                        ______________________________________                                        Variation of Ratios of Permeation Rates                                       Depending on Thickness of Adhesive Layer                                                             Ratio of Permeation                                               Thickness of                                                                              Rates                                                  Formulation                                                                              Adhesive Layer                                                                            Norethindrone/Ethinyl                                  Number     (Microns)   Estradiol                                              ______________________________________                                        2-22       142.8        3.92 (± 0.52)                                      2-23       178.5        8.00 (± 1.33)                                      2-24       214.2       12.27 (± 2.02)                                      2-7        250.0       18.33 (± 2.34)                                      2-25       285.6       18.03 (± 2.17)                                      2-26       321.7       17.16 (± 1.99)                                      ______________________________________                                    

The following Tables 14 and 15 show data for dosage units withoutseparating layers in comparison with data shown in Tables 5 and 6 fordosage units with separating layers.

                                      TABLE 14                                    __________________________________________________________________________    Drug Recovery Data from Stability Samples of Bi-Layer Patch                   System.sup.(2)                                                                       Sampling Time (Weeks After Storage)                                    Temperature                                                                          0    1   2   4   8   12   26                                           __________________________________________________________________________    Ethinyl Estradiol (mcg/10 cm.sup.2 ± S.D.).sup.(1)                         Room Temp.                                                                           566.9                                                                              --  -   569.4                                                                             536.8                                                                             552.2                                                                              539.9                                               (33.18)      (34.44)                                                                           (33.90)                                                                           (33.11)                                                                            (35.56)                                      37° C.                                                                        572.5                                                                              --  570.0                                                                             545.1                                                                             557.5                                                                             539.9                                                                              533.6                                               (40.26)  (34.67)                                                                           (41.11)                                                                           (31.22)                                                                           (33.31)                                                                            (29.98)                                      45° C.                                                                        559.4                                                                              566.9                                                                             530.5                                                                             527.7                                                                             510.0                                                                             519.8                                                                              507.6                                               (38.88)                                                                            (44.76)                                                                           (39.77)                                                                           (41.12)                                                                           (44.17)                                                                           (36.66)                                                                            (38.98)                                      Norethindrone (mcg/10 cm.sup.2 ± S.D.).sup.(1)                             Room Temp.                                                                           15.52                                                                              --  --  14.98                                                                             14.16                                                                             15.78                                                                              16.12                                               (0.99)       (0.92)                                                                            (0.79)                                                                            (1.05)                                                                             (1.11)                                       37° C.                                                                        16.11                                                                              --  16.64                                                                             15.52                                                                             14.22                                                                             15.78                                                                              14.02                                               (1.19)   (0.84)                                                                            (0.91)                                                                            (0.77)                                                                            (1.17)                                                                             (0.69)                                       45° C.                                                                        17.72                                                                              17.01                                                                             15.24                                                                             14.96                                                                             14.66                                                                             15.28                                                                              14.06                                               (1.27)                                                                             (1.00)                                                                            (0.92)                                                                            (1.33)                                                                            (1.07)                                                                            (1.26)                                                                             (0.93)                                       __________________________________________________________________________     .sup.(1) Mean ±  Standard Deviation (N = 3).                               .sup.(2) Triplicate sample dosage units solvent extracted at indicated        storage times and temperatures and the ethinyl estradiol and norethindron     contents determined using high performance liquid chromatography (HPLC). 

                                      TABLE 15                                    __________________________________________________________________________    Skin Permeation Rate from Stability Samples of Bi-Layer Patch                 System.sup.(2)                                                                       Sampling Time (Weeks After Storage)                                    Temperature                                                                          0    1   2   4   8   12   26                                           __________________________________________________________________________    Ethinyl Estradiol (mcg/10 cm.sup.2 hr ± S.D.).sup.(1)                      Room Temp.                                                                           0.59 --  --  0.52                                                                              0.55                                                                              0.59 0.64                                                (0.04)       (0.06)                                                                            (0.05)                                                                            (0.04)                                                                             (0.08)                                       37° C.                                                                        0.61 --  0.63                                                                              0.70                                                                              0.73                                                                              0.66 0.79                                                (0.08)   (0.09)                                                                            (0.07)                                                                            (0.11)                                                                            (0.10)                                                                             (0.14)                                       45° C.                                                                        0.66 0.69                                                                              0.76                                                                              0.77                                                                              0.74                                                                              0.77 0.87                                                (0.11)                                                                             (0.13)                                                                            (0.13)                                                                            (0.08)                                                                            (0.09)                                                                            (0.16)                                                                             (0.12)                                       Norethindrone (mcg/10 cm.sup.2 hr ± S.D.).sup.(1)                          Room Temp.                                                                           2.51 --  --  2.58                                                                              2.44                                                                              2.31 2.20                                                (0.21)       (0.26)                                                                            (0.31)                                                                            (0.13)                                                                             (0.23)                                       37° C.                                                                        2.88 --  2.95                                                                              2.39                                                                              2.33                                                                              2.22 2.07                                                (0.21)   (0.20)                                                                            (0.15)                                                                            (0.17)                                                                            (0.12)                                                                             (0.11)                                       45° C.                                                                        2.74 2.61                                                                              2.50                                                                              2.31                                                                              1.92                                                                              2.05 2.01                                                (0.33)                                                                             (0.22)                                                                            (0.16)                                                                            (0.15)                                                                            (0.25)                                                                            (0.31)                                                                             (0.11)                                       __________________________________________________________________________     .sup.(1) Mean ± Standard Deviation (N = 3).                                .sup.(2) Permeation rate of triplicate sample dosage units determined         using 5-7 week old female hairless mouse skin in Chien et al. procedure       for 146 hours and the rates determined from slope of Q vs permeation time     plots.                                                                   

EXAMPLE 9

The procedure of Example 8 is followed to provide other transdermaldosage units of this invention: 1) 17-betaestradiol in combination withnorethindrone or norgestimate, 2) ethinyl estradiol-norgestimatecombination, and 3) the other combinations with progestins and estrogensselected from those named above, with the skin permeation ratesnecessary to provide the desired daily dose for fertility control orestradiol replacement. Also, the above dosage units of this Example andExample 8 are repeated using the other adhesives and polymers namedabove.

What is claimed is:
 1. A transdermal estrogen/progestin dosage unitcomprising:(a) a backing layer which is substantially impervious to theestrogen and progestin hormones to be delivered transdermally; (b) apolymer layer which is adhered to said backing layer and which hasdissolved and/or microdispersed therein an effective dosage amount ofone or more effective estrogens absorbable transdermally and arepharmaceutically acceptable, said polymer being bioacceptable, providinga compatible enviroment for said one or more estrogens and permittingsaid one or more estrogens to be transmitted for transdermal absorption,and (c) an adhesive layer in intimate contact with said polymer layer,said adhesive layer having dissolved and/or microdispersed therein aneffective dosage amount of one or more effective progestins, which areabsorbable transdermally and are pharmaceutically acceptable, saidadhesive layer being bioacceptable, providing a compatible enviromentfor said one or more progestins, and permitting said one or moreprogestins and said one or more estrogens to be transmitted fortransdermal absorption, said adhesive layer having an effective amountof transdermal skin absorption enhancing agent; said hormones beingstable in said polymer and adhesive layers and being transdermallyabsorbed simultaneously to provide at least minimum effective dailydoses of said hormones to effect fertility control or estrogenreplacement therapy.
 2. A transdermal dosage unit of claim 1 which hasethinyl estradiol or 17-beta-estradiol or combinations thereof as saidone or more estrogens.
 3. A transdermal dosage unit of claim 1 which hasnorethindrone or norgestimate or combinations thereof as said one ormore progestins.
 4. A transdermal dosage unit of claim 1 which hasethinyl estradiol as said estrogen and norethindrone or norgestimate assaid progestin.
 5. A transdermal dosage unit of claim 1 which has17-beta-estradiol as said estrogen and norethindrone or norgestimate assaid progestin.
 6. A transdermal dosage unit of claim 1 in which saidadhesive layer or said polymer layers or both layers are made from apolyacrylic adhesive polymer.
 7. A transdermal dosage unit of claim 6 inwhich said polyacrylic adhesive polymer has the following formula:##STR5## wherein x represents the number of repeating units sufficientto provide the defined properties of said adhesive layer or polymerlayer or both layers and R is selected from H or lower alkyl.
 8. Atransdermal dosage unit of claim 1 in which the backing layer ismicroporous and breathable.
 9. A transdermal dosage unit of claim 1 inwhich said adhesive layer or polymer layer or both layers are made froma silicone adhesive polymer or a polyisobutylene adhesive polymer.
 10. Atransdermal dosage unit of claim 1 in which the Enhancing Factor withregard to said progestin is at least 1.2, 1.3, 1.5 or 2.0.
 11. Atransdermal dosage unit of claim 1 wherein the transdermal skinabsorption enhancing agent is n-decyl alcohol.
 12. A transdermal dosageunit of claim 1 which effectively provides at least minimum daily dosageamounts of said estrogen and progestin for about one week, having anamount of said skin permeation absorption enhancing agent to provide anEnhancing Factor of at least about 1.5 with regard to said progestin.13. A transdermal dosage unit of claim 1 wherein said polymer layerhaving present one or more estrogens and said adhesive layer havingpresent one or more progestins are separated by, but are in respectiveintimate contact therewith, a bioacceptable adhesive or polymerseparating layer through which said one or more estrogens aretransmitted for desired transdermal absorption, said separating layermade using an adhesive or polymer which is free or substantially free ofestrogen, progestin and enhancing agents.
 14. A transdermal dosage unitof claim 13 which has ethinyl estradiol or 17-beta-estradiol orcombinations thereof as said one or more estrogens and norethindrone ornorgestimate or combinations thereof as said one or more progestins. 15.A transdermal dosage unit of claim 13 wherein the separating layer ismade from a bioacceptable adhesive or polymer having a sufficiently highviscosity or molecular weight to provide a dimensionally stableseparating layer and a substantial reduction in the transmission rate ofsaid one or more estrogens.
 16. A transdermal dosage unit of claim 15where the separating layer is made from a polyisobutylene adhesive. 17.A transdermal dosage unit of claim 15 wherein the ratio of transdermallyabsorbed progestin to estrogen hormones is in the range of about 10/1 toabout 30/1.
 18. A transdermal dosage unit of claim 17 wherein the ratioof transdermally absorbed progestin to estrogen hormones is in the rangeof about 12/1 to about 20/1.
 19. A transdermal dosage unit of claim 17wherein the separating layer is made from polyisobutylene.
 20. Atransdermal dosage unit of claim 18 wherein the separating layer is madefrom polyisobutylene having a relative molecular mass M_(V) (viscosityaverage) of from about 800,000 to about 900,000.
 21. A transdermaldosage unit of claim 17 which has ethinyl estradiol or 17-beta-estradiolor combinations thereof as said one or more estrogens and hasnorethindrone or norgestimate or combinations thereof as said one ormore progestins.
 22. A transdermal dosage unit of claim 21 wherein theadhesive or polymer is a bioacceptable polyisobutylene.
 23. Atransdermal dosage unit of claim 22 where the separating layer has athickness of from about 75 to about 125 microns and the polyisobutylenehas a relative molecular mass M_(V) (viscosity average) of at leastabout 800,000.